Pro-Oncogenic Role of a Mitochondrial Lipid Kinase in CLL

线粒体脂质激酶在 CLL 中的促癌作用

• 批准号: 10651077
• 负责人: Asish Kumar Ghosh
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651077
• 关键词: Accounting; Adult; Agammaglobulinaemia tyrosine kinase; Antigens; Applications Grants; Automobile Driving; B lymphoid malignancy; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; BCL2 gene; Behavior; Binding; Biological; Biological Process; Blood; Bone Marrow; Cell Proliferation; Cell Survival; Cells; Cellular biology; Cervical Squamous Cell Carcinoma; Chronic Lymphocytic Leukemia; Clinical; Cytoplasm; Data; Dedications; Diagnosis; Diglycerides; Disease; Disease Progression; Early treatment; Epigenetic Process; Esophageal Squamous Cell Carcinoma; Event; FRAP1 gene; Genetic; Genetic Transcription; Goals; Heterogeneity; Human; In Vitro; Indolent; Induction of Apoptosis; Investigation; JAK2 gene; LYN gene; Lipids; Liposomes; Malignant - descriptor; Malignant neoplasm of prostate; Mediating; Mediator; Mitochondria; Molecular; Monoglycerides; Nuclear; Oncogenes; Oncogenic; Oral; Organ; PI3K/AKT; PIK3CG gene; PTEN gene; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphatidic Acid; Phosphotransferases; Process; Production; Proliferating; Proto-Oncogene Proteins c-akt; Public Health; Receptor Inhibition; Receptor Signaling; Regulation; Resistance; Richter' s Syndrome; Risk Factors; Role; STAT3 gene; Signal Transduction; Signaling Molecule; Small Interfering RNA; Spleen; Squamous cell carcinoma; Testing; Therapeutic; Time; Transgenic Mice; Treatment outcome; Tumor Burden; Up-Regulation; cell growth; cell type; chronic lymphocytic leukemia cell; clinical heterogeneity; cohort; cytotoxic; high risk; improved; in vivo; inhibitor; inhibitor therapy; innovation; insight; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; lymph nodes; lysophosphatidic acid; malignant breast neoplasm; mitochondrial membrane; mouse model; novel; overexpression; prognostic; relapse patients; survival outcome; targeted agent; targeted treatment; therapeutic target; therapy outcome; therapy resistant; tumor; tumorigenesis

PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is an adult B-cell malignancy accounting for about a third of leukemia diagnoses in the US. While B-cell receptor (BCR)-signal-inhibitors are changing the management of CLL, these are not curative and resistance can develop; often leading to more aggressive disease. Given this, understanding the molecular events driving CLL oncogenesis and therapeutic resistance warrants in-depth investigation. CLL is a disease characterized by extensive clonal proliferation and accumulation of malignant B lymphocytes in the blood, bone marrow, spleen, and lymph nodes. CLL shows remarkable clinical heterogeneity, with some patients pursuing an indolent course, while others progress rapidly and require early treatment. In the past 10 years, new insights into the biological function of a mitochondrial lipid kinase, acylglycerol kinase (AGK), as a key oncogene that is highly expressed in a range of tumor types, including prostate cancer, breast cancer, cervical squamous cell carcinoma, and esophageal squamous cell carcinoma have been established. Most recently, we found aberrantly high level expression of AGK in CLL cells from ~60% of pre-therapy CLL patients. However, the mechanism of aberrant upregulation of AGK in CLL cells, and its precise functional contributions to CLL cell biology and pathogenesis remain unknown. Interestingly, we detected nuclear/cytoplasmic localization of AGK in some CLL clones suggesting its multi-functional role. In line with this, we found that siRNA- mediated depletion of AGK in primary CLL cells resulted in marked inhibition of constitutively active multiple signal mediators including AKT, Erk1/2, LYN, BTK (downstream targets of BCR signal) and JAK2. Our preliminary findings also indicate that MYC may regulate AGK expression in CLL cells. Our combined data suggest that aberrant expression of AGK may potentiate cell survival signals including BCR and JAK2 in some CLL clones resulting in resistance to BCR-targeted therapies. Therefore, the central hypothesis of this application is that aberrant expression of AGK in some CLL clones represents highly aggressive CLL with shorter time to therapy. We also postulate that AGK upregulation potentiates CLL cell survival signals and resistance to BCR- targeted agents. We propose – Aim 1: Evaluate if aberrant expression of AGK in CLL cells drives disease progression; Aim 2: Define the mechanism of AGK upregulation and its role in CLL cell biology, signaling and potential as a therapeutic target. The proposed in-depth studies will assess if “high AGK” level in CLL cells serves as a risk factor for CLL progression, time to therapy and treatment outcome; define the impact of AGK aberrant expression on CLL cell survival and resistance to current BCR-targeted therapies. Thus, the proposed studies have enormous potential to establish a new prognostic parameter and therapeutic avenue via targeting AGK in CLL cells with or without the current BCR-targeted therapy, ibrutinib.

项目总结 慢性淋巴细胞性白血病(CLL)是一种成人B细胞恶性肿瘤，约占白血病的三分之一 在美国的诊断。虽然B细胞受体(BCR)信号抑制剂正在改变CLL的管理，但这些 不能治愈，会产生抗药性；通常会导致更具侵袭性的疾病。有鉴于此，理解 驱动CLL肿瘤发生和治疗耐药的分子事件值得深入研究。 CLL是一种以广泛的克隆性增殖和恶性B淋巴细胞聚集为特征的疾病 在血液、骨髓、脾和淋巴结中。CLL表现出显著的临床异质性，有一些 患者追求缓慢的疗程，而其他患者进展迅速，需要早期治疗。在过去10年中 多年来，人们对线粒体脂肪激酶--甘油酰基激酶(AGK)的生物学功能有了新的认识。 在一系列肿瘤类型中高表达的关键癌基因，包括前列腺癌、乳腺癌、 宫颈鳞癌和食道鳞状细胞癌已经成立。多数 最近，我们发现约60%的治疗前CLL患者的CLL细胞中AGK的表达异常高。 然而，在CLL细胞中AGK异常上调的机制及其确切的功能贡献 对CLL的细胞生物学和发病机制尚不清楚。有趣的是，我们检测到了细胞核/细胞质 AGK在一些CLL克隆中的定位表明其具有多功能作用。与此相一致，我们发现siRNA- 在原代CLL细胞中介导的AGK耗竭导致对构成活性多倍体的显著抑制 信号介体包括AKT、ERK1/2、LYN、BTK(BCR信号的下游靶标)和JAK2。我们的 初步研究结果还表明，MYC可能调节CLL细胞AGK的表达。我们的综合数据 提示AGK的异常表达可能增强了包括bcr和JAK2在内的一些细胞生存信号。 CLL克隆导致对bcr靶向治疗的抵抗。因此，这一应用程序的中心假设 AGK在某些CLL克隆中的异常表达代表了高度侵袭性的CLL，其发病时间较短 心理治疗。我们还假设AGK上调增强了CLL细胞的生存信号和对bcr-1的耐药性。 目标特工。我们建议-目标1：评估在CLL细胞中AGK的异常表达是否会导致疾病 目的2：明确AGK上调的机制及其在CLL细胞生物学、信号转导和免疫调节中的作用 作为治疗靶点的潜力。拟议的深入研究将评估CLL细胞中“高AGK”水平是否起作用 作为慢性淋巴细胞白血病进展、治疗时间和治疗结果的危险因素；确定AGK异常的影响 CLL细胞存活和对当前bcr靶向治疗的耐药性的表达。因此，拟议的研究 具有通过靶向AGK建立新的预后参数和治疗途径的巨大潜力 使用或不使用当前bcr靶向治疗ibrutinib的CLL细胞。